Though most advanced solid tumors initially respond to genotoxic chemotherapy and/or radiation, the development of resistance is common and portends a poor outcome. This proposal will test the hypothesis that DNA damage in the tissue microenvironment, induced by cancer therapeutics, promotes detrimental tumor cell phenotypes (therapy resistance) through cell non-autonomous mechanisms dictated by non-neoplastic resident cell types. We further hypothesize that inhibiting specific components of this DNA damage secretory program (DDSP) will attenuate therapy resistance and enhance tumor responses. We propose to test this hypothesis through three specific aims. Aim 1 will determine the ability of specific paracrine-acting DNA-damage Secretory Program (DDSP) proteins to modulate adverse tumor cell behaviors (e.g. therapy resistance) and determine the mechanism(s) by which they do so. Aim 2 will determine the intracellular signal transduction programs that differentially modulate subsets of effector proteins comprising DDSP. Aim 3 will determine the consistency of the DDSP across different tumor types and establish the temporal and cell type-specific variability of damage response programs. The successful completion of these aims will alter current concepts of treatment resistance, both to genotoxic and to pathway directed (e.g. EGFR) therapeutics, by shifting the emphasis from intrinsic tumor cell alterations (rare, clonally-selected events) to a context-dependent (genotoxic damage) microenvironment influence on tumor cell phenotypes. Determining the mechanisms by which the DDSP promotes therapy resistance will provide rationale for co-targeting specific DDSP components and/or their regulatory nodes to mitigate microenvironment signals that promote both intrinsic tumor cell programs of resistance (e.g. EMT) and collective effects such as enhanced tumor cell repopulation kinetics. PUBLIC HEALTH RELEVANCE: The tumor microenvironment (TME) is increasingly recognized as a major contributor to the development and progression of malignant neoplasms. We propose to evaluate the original concept that conventional cancer therapeutics, such as ionizing radiation and alkylating drugs, which exert anti-tumor effects through DNA damage, modify the TME to enhance resistance to subsequent treatments, and consequently promote adverse cancer phenotypes.